Certain amides of 5h-dibenzo [a, d] cycloheptene- and 10, 11-dihydro-5h-dibenzo [a, d] cycloheptene-5-carboxylic acid



United States Patent 3,344,185 CERTAIN AMIDES 0F SH-DIBENZO [A,D] CYCLO-HEPTENE- AND 10,11 DIHYDRO-SH-DIBENZO [A,D] CYCLOHEPTENE-S-CARBOXYLICACID Frederick Leonard, 14103 Gaines Ave., Rockville, Md. 20853 NoDrawing. Filed Get. 20, 1965, Ser. No. 499,004 2 Claims. (Cl. 260--558)general formula:

H COABNRR: I

wherein Y stands for the ethylene or vinylene group, CH CH or CH CHrespectively,

A represents 0 or NH,

B stands for lower alkylene,

R and R are hydrogen or lower alkyl,

NRR is a heterocyclic moiety, such as pyrrolidino,

piperidino, piperazino, N-(lower) alkyl-piperazino, morpholino,thiomorpholino The term lower alkyl as used herein means saturatedmonovalent aliphatic radicals of the general formula C H wherein mdesignates an integer of less than 6 and is inclusive of both straightchain and branched chain radicals.

The term lower alkylene as used herein means saturated divalentaliphatic groups of the general formula H wherein n designates aninteger of from 2 to 6 and is inclusive of both straight and branchedchain radicals.

Briefly, the compounds of this invention may be synthesized readily byreacting carboxylic acids or acid halides of the formula:

/ X H COX wherein X represents hydroxy or halogen, particularly chlorineor bromine, and Y has the definition ascribed to it hereinabove with adior mono(lower)alkylaminoor heterocyclic lower alkanol or -lower alkylhalide of the formula:

ZBNRR wherein Z is OH or halogen, particularly chlorine or bromine andB, R, R and NRR have the meanings given to them above.

More specifically, the subject compounds may be made by the followingmodes of preparation:

(A) 5-carb0xylaze derivatives Such compounds may be formed by refluxingthe above defined S-carboxylic acids with a basically substituted loweralkyl halide in a lower alkanoic medium furnished, e.g. by methanol,ethanol, propanol, etc., from about 2 hours to about 20 hours andpreferably, for about 12 hours.

Alternatively, such S-carboxylate derivatives are prepared by refluxingan acid halide as defined above with a basically substituted loweralkanol in a reaction medium such as is provided by benzene, chloroform,carbon tetrachloride, carbon disulfide, etc. for from about 1 hour toabout 20 hours and preferably for about 2 hours.

S-carboxylate derivatives of Formula I wherein R is hydrogen and Rrepresents lower alkyl may be prepared in several ways. For instance,treatment of an acid halide as defined above, with a secondaryamino(lower) alkanol in a reaction medium constituted by such solventsas benzene, chloroform, carbon tetrachloride, carbon disulfide, etc.lasting for from about 1 hour to about 20 hours and preferably for about4 hours, yields an N-(lower) alkyl-N-hydroxy(lower)alkyl 5Hdibenzo[a,d]cyclohepteneor 10,11-dihydro 5H-dibenzo[a,d] cycloheptene-S-carboxamide which when subjected to concentrated hydrochloric acid isconverted to the desired mono(lower) alkylamin-o(lower) alkyl esters.

Alternatively, dealkylation of a S-carboxylate derivative of Formula Iwherein R and R are alkyl gives the desiredmono(lower)alkylamino(lower)alkyl esters, as for instance by treatmentwith ethyl chlorocarbonate to form a urethane derivative which uponsaponification gives the desired dcalkylated compound.

Further, such mono (lower)alkylamino(lower) alkyl esters can also beobtained by hydrogenolysis of a S-carboxylate derivative of Formula Iwhere, however, R represents benzyl in the presence of a noble metalcatalyst, such as, palladium on charcoal, platinum, etc.

(B) S-carboxamide derivatives These compounds are made by refluxing thecarboxylic acid chlorides, mentioned above, with an appropriatelysubstituted lower alkylene diamine, in a reaction medium exemplified bybenzene, chloroform, carbon tetrachloride, carbon disulfide, etc. forabout 1 hour to about 20 hours and preferably about 2 hours.

S-carboxamide derivatives of Formula I wherein R is hydrogen and Rrepresents lower alkyl can be synthesized by using the above-describedtreatment with ethyl chlorocaroonate of compounds of Formula I whereinboth R and R are lower alkyl and by saponification of the intermediatesobtained or hydrogenolysis of compounds of Formula I wherein Rrepresents benzyl in the presence of noble metal catalysts.

The starting materials are either commercially available, as forexample, the above mentioned alkyl halides, alkanols and diamines or, asin the case of the above identified S-carboxylic acid and S-earboxylicacid halide derivatives, can be readily prepared in accordance with thefollowing syntheses:

(l) Benzylidene-phthalic anhydride prepared from phthalic anhydridephenylacetic acid according to Org. Synth. COIL, vol. 2, I. Wiley, N.Y.,1943, p. 61, is hydrogenated in absolute dioxane in the presence of anickelcatalyst until the hydrogenation is completed and 2- phenylethylbenzoic acid is obtained.

(2) To this benzoic acid derivative percent polyphosphoric acid is addedat about C. The reaction mixture is then stirred for about 2 hours.10,11-dihydro- 5H-dibenzo[a,d]cycloheptene-S-one is obtained inconsequence of this procedure.

(3) By adding sodium in absolute ethanol to this ketone under drynitrogen with vigorous stirring, 10,11-dihydro-SH-dibenzo[a,d]cycloheptene is formed after refluxing for about /2 hourto about 4 hours and preferably for about 1 hour.

(4a) The desired carboxylic acid10,11-dihydro-H-dibenzo[a,d]cycloheptene-Scarboxylic acid is made byadding butyl-lithium in wax to a mechanically stirred solution of thereaction product of step three in absolute ether under dry oxygen-freenitrogen, refluxing the reaction mixture for about /2 hour to about 4hours and then adding carbon dioxide to the reaction mixture.

(4b) The desired 5H-dibenzo[a,d]cycloheptene-S-carboxylic acid isobtained, for example, by (1) brominating the product of step three bymeans of N-br-omo-succinimide in the presence of benzoyl peroxidedissolved in carbon tetrachloride under reflux conditions, (2)dehydrobrominating the compound obtained by heating with pyridine and(3) treating the 5H-dibenzo[a,d]cycloheptene thus formed as describedunder (4a) above.

(5) By treating the above carboxylic acids with, for example, thionylhalides or phosphorous halides, the corresponding 5-carboxylic acidhalide derivatives are obtained which can be converted to theS-carboxamide derivatives by treatment with ammonia.

The present invention comprehends not only the abovedescribedderivatives of 5H-dibenzo[a,d]cycloheptene and10,1l-dihydro-SH-dibenzo[a,d]cycloheptene in their free base form, butit also include pharmaceutically ac- 'ceptable non-toxic acid additionsalts which may be fiormed from said compounds in accordance withconventional practice, by using appropriate inorganic and organic acids,such as hydrohalic acids, especially hydrochloric and hydrobromic acids,sulfuric, methane-sulfonic and phosphoric acids as well as acetic,aminoacetic, lactic, succiuic, malic, aconitic, phthalic and tartaricacids.

The quaternary ammonium salts of compounds of the present invention,which are pharmaceutically acceptable, can be obtained by addition tothe corresponding free bases of alkyl or aralkyl esters of inorganicsulfoni-c acids, including such compounds as methyl chloride, methylbnomide, methyl iodide, ethyl bromide, propyl bromide, octyl bromide,benzyl chloride, benzyl bromide, methyl sulfate, methylbenzenesulfonate, and methyl p-toluenesulfonate, giving themethochloride, methobromide, meth. oiodide, ethobromide, propobromide,octobromide, benzochloride, benzobromide, methosulfate,methobenzenesulfonate, and metho-p-toluene sulfonate salts,respectively.

As mentioned above, the subject compounds possess valuablepharmacological properties; they exhibit anticonvulsant, spasmolytic andanti-epileptic activity and can thus be used as anticonvulsant,spasmolytic and antiepileptic agents. They also are effective localanesthetic agents.

Merely by illustration, Z-diethylaminoethyl 10,11-dihydro-SH-dibenzo[a,d]cycloheptene 5 carboxylate hydrochloride provides for example, whenadministered to mice in doses of 100 mg./kg. p.o., 100% protectionagainst electro-shock for more than 4 /2 hours and delays at the samedose the onset of convulsions and death brought about by metrazole.

As is obvious to those skilled in the art the subject compounds can beadministered as pharmaceutical com positions in dosage unit form.

These new compounds, and the methods for their preparation may beexemplified more fully by the following illustrative examples. Thetemperatures therein are given in degrees centigrade.

EXAMPLE I Z-dimethylaminoethyl 10,11-dihydro-5H-dibenzo [a,d]cycl0heptene-5-carboxylate hydrochloride (1) 2 (ph-enylethyl) benzoicacid.-Benzylidenephthalic anhydride (33 g., 1.5 moles) preparedaccording to Org. Synth. C-oll., vol. 2, J. Wiley, N.Y., 1943, p. 61,was hydrogenated in 250300 ml. of absolute diioxane, obtainedperoxide-free by chromatography on basic aluminum oxide, in the presenceof 60 g. Girdler stabilized nickel-catalyst. The starting hydrogenpressure was 1700 p.s.i. at 25 0, corresponding to 2880 p.s.i. at 400 K.After shaking for 3 hours at the latter temperature the pressure was1330 p.s.i., corresponding to a hydrogen uptake of 92%. The crude,crystalline reaction mixture was washed out with absolute dioxane,filtered through Celite and evaporated. Dissolving the resulting residuein 5 N ammonia-Water, filtration and precipitation with cone. HCl at 0under vigorous stirring resulted in 265 g. of slightly beige crystals,M.P. 11812S; v(CCl C=O 1770 and 1690 cmf Recrystallization from ether/pentane gave 249 g. of pure phenylethylbenzoic acid; M.P. 128-130",v(CCl C=O 1760 cmf e(MeOI-I) 2780 A., 1300, equivalent weight calc. 226,found 227.

(2) 10,11 dihydro 5H dibenzo[a,d] cyclolzeptene-S-one.2-(phenylethyl)-benzoic acid (90.4 g., 0.4 mole) was added to 4 kg.of polyphosphoric acid at After stirring at this temperature for 2 hoursthe reaction mixture was poured on 4 kg. ice with stirring and extractedwith three 1 lt. portions of ether. The combined extracts were washedtwice with 500 ml. of 2 N Na CO thrice with 500 ml. of icewater, driedover anhydrous MgSO and evaporated. Distillation of the brown residueyielded 70 g. of the desired ketone, B.P. 0.4 Torr n 16330-16332; M.P.3233 (from MeOH at 0), v(liq.) C=O 1650 cm. e(MeOH) 2670 A., 16,000,e(cy-clohex.) 2630 A., 18,000 e(isooctane) 2640 A., 16,600.

(3) 10,11 dihydrm- 5H dibenzo [a,d]cycl0heptene.- Sodium (46.0 g., 2.0moles) was added to 45.0 g. (0.216 mole) of the above ketone in 900 ml.absolute ethanol under dry nitrogen with vigorous stirring. Afterrefluxing for 30 min. the reaction mixture was cooled, treated with 1It. of icewater and extracted with two lt. of portions of ether. Theorganic phase was then washed twice with 1 lt. water, dried over MgSOand evaporated. Crystallization of the residue from ethanol yielded29.56 g. of the desired reaction product; M.P. 72-75.

(4a) 10,11 dihydro 5H dibenz0[a,d]cycl0heptene- S-carboxylicacid.Butyl-lithium (44.0 g., 0.136 mole, 20.0%) in wax was added to amagnetically stirred solution of 22.4 g. (0.115 mole) of the abovecycloheptene in 250 ml. absolute ether under dry, oxygen-free(Fiesersolution) nitrogen. After heating to reflux for 1.5 hours thebrown mixture was added to 300 g. finely crushed CO under vigorousstirring and simultaneous addition of 500 ml. of absolute ether.Stirring was continued on a waterbath for 30 min, after which all the COhad evaporated. Addition of 300 ml. 0.4 N Na CO solution was followed bywashing with three 250 ml. portions of ether. Separation andacidification of the aqueous phase with ice cold 2 N HCl under 500 ml.ether, extraction with another 500 ml. of ether, drying of the organicphase over MgSO evaporation and recrystallization from CHCl /pentanegave 17.95 g. of the desired carboxylic acid; M.P. 215- 218, vKBr C=O,1690 cmf (4b) 10,11 dihydro 5H dibenzo[a,d]cycl0heptene- 5-carboxylz'cacid chl0rz'de.-The above carboxylic acid (2.38 g., 0.01 mole) wasrefluxed in 20 ml. of thionyl chloride with magnetic stirring underargon for one hour. After evaporation to dryness and recrystallizationfrom pentane, 2.0 g. of the desired acid chloride was obtained; M.P.64-65", C=O, CHCI 1800, 1775 cm.- CDCl 3.02 (8H), 5.08 (1H), 7.04 (4H).

(5) Z-dimethylaminoethyl 10,11-dihydr0 5H dibenzo [a,d]cycloheptene 5-carb0xylate hydr0chl0ride.l0,1ldihydro-SH-dibenzo [a,d]cycloheptene 5carboxylic acid (11.9 g., 0.05 mole) was dissolved in 200 m1. ofbenzene. To the solution was added 50 ml. of thionyl chloride. Themixture was refluxed for 18 hours and then concentrated in vacuo to anoily residue which was taken up in benzene and again concentrated to asyrup. The syrup was dissolved in 100 ml. of benzene and 4.4 g. (0.05mole) of dimethyl-aminoethanol in 50 ml. of benzene was added dropwiseat room temperature. The reaction was stirred and refluxed for 4 hours.The reaction mixture was cooled and the desired compound was filteredoff as white crystals. After recrystallization from ethanol it melted at210- 212. Yield: 7 g.

Analysis.-For C H ClNO -Calcd: C, 69.47; H, 6.99; N, 4.05. Found: C,69.39; H, 7.04; N, 4.08.

EXAMPLE II 2- (1 0,11-dihydro-5H-dibenzo [a,d] cycloheptene-5- carboxyethyldimezhylocty[ammonium bromide 2-diemthylaminoethyl 10,1l-dihydro-SH-dibenzo [a,d] cycloheptene-S-carboxylate hydrochloride (5g.) was dissolved in 15 ml. of water. The solution was cooled to 5, thepH adjusted to 10 with 10% NaOH and the liberated oil was extracted withether. The ether extract was dried over anhydrous Na SO Concentration ofthe dried extract gave 4 g. of Z-dimethylaminoethyl 10,11-dihydro-SH-dibenzo [a,d] cycloheptene-5-carboxylate.

Z-dimethylaminoet'nyl 10,1 l-dihydro-SH-dibenzo[a,d]cycloheptene-S-carboxylate (4 g.) was dissolved in 100 ml. of dryacetone. To the solution was added the equivalent amount of octylbromide (2.8 g.). The mixture was refluxed for 28 hours and thenconcentrated. The oily residue that was obtained crystallized onaddition of ether (cooling). After recrystallization from a mixture ofethyl acetate and ether, the desired ammonium salt melted at 8587; yield2.5 g.

Analysis.-For C H BrNO Calcd: C, 66.95; H, 8.19; N, 2.78. Found: C,67.24; H, 8.21; N, 3.01.

EXAMPLE III Z-diethylaminoethyl 10,1I-dihydr-5H-dibenzo [a,d]cycloheptene-S-carboxylate hydrochloride The carboxylic acid of ExampleI (4a) (10.70 g., 0.045 mole) and 6.10 g. (0.045 mole) ofZ-diethylaminoethyl chloride in 90 ml. of dry isopropanol were heated toreflux for 12 hours. Upon cooling in ice the reaction product (16.47 g.)precipitated. After recrystallization from the same solvent and washingwith absolute ether and drying, the desired compound melted at 195-197",rKBl' C=O 1740 GEL-1.

Analysis-For C H ClNO -Calcd: C, 70.66; H, 7.56; N, 3.75. Found: C,70.35; H, 7.77; N, 3.49.

EXAMPLE IV 2- 1 0,1 1 -d ihydr0-5 H -di benzo [a,d cycloh epten e--carboxy ethyldiethylmethy lamm'oni um iodide The compound of ExampleIII (7.90 g., 0.21 mole) was dissolved in 25 ml. 2 N ice cold NaOH andextracted thrice with 100 ml. ether. The combined extracts were driedover K CO evaporated to 50 ml. and treated dropwise with 3.12 ml. (0.05mole) freshly distilled methyl iodide in 50 ml. of absolute ether at 0under vigorous stirring. The resulting precipitate, 7.89 g. of whitecrystals was filtered and recrystallized from acetone and ether, M.P.156-158", vKBr, C=O 1740 crnf Analysis.For C H INO Calcd: C, 57.70; H,6.31; N, 2.92. Found: C, 57.68; H, 6.46; N, 8.82.

EXAMPLE V N 2 (diethylaminoethyl) 10,1I-dihydro-SH-dibenz-[a,d]cyclohepzene-S-carboxamide hydrochloride monohydrate The carboxylicacid of Example I (4a) (9.2 g., 0.04 mole) was dissolved in 160 ml. ofbenzene and treated slowly with 20 ml. of thionyl chloride. The mixturewas refluxed for 18 hours and concentrated to a syrupy residue in vacuo,which was taken up in benzene and again concentrated to a syrup. Thesyrup was dissolved in 100 ml. of benzene and 4.7 g. (0.04 mole) ofN,N-diethylethylenediamine in 500 ml. of benzene were added dropwise atroom temperature. The reaction mixture was stirred and refluxed for 4hours. Upon cooling crystals separated, which, after recrystallizationfrom a mixture of isopropanol and ethanol (8:2) melted at 133-135 yield6.7 g.

Analysis.For C H ClN O Calcd: C, H 8.00; N, 7.16. Found: C, 67.79; H,8.35; N, 7.00.

EXAMPLE VI 3-diethylaminopropyl 10,11-dihydro-5H-dibenzo [a,d]cycloheptene-S-carboxylate hydrochloride The carboxylic acid of ExampleI (4a) (8 g., 0.033 mole) was dissolved in ml. of benzene. To thesolution was added 30 ml. of thionyl chloride. The mixture was refluxedfor 18 hours, and then concentrated in vacuo to an oily residue whichwas taken up in benzene and again concentrated to a syrup. The syrup wasdissolved in 50 ml. of benzene and treated with 4 g. (0.033 mole) of 3-diethylamino-l-propanol in 25 ml. of benzene, added dropwise at roomtemperature. The reaction was stirred and refluxed for 3.5 hours. Thereaction mixture was cooled and diluted with 100 ml. of ether. A mixtureof gum and crystals precipitated. The mixture of solvents was decantedand the residue was crystallized from ethyl acetate. The crystallineproduct melted at 147-148; yield 3.5 g.

Analysis.For C H ClNO Calcd: C, 71.19; H, 7.79; N, 3.61. Found: C,70.83; H, 8.16; N, 3.76.

EXAMPLE VII 3-diethylamino-2-propyl 10,11-dihyar0-5H-dibenz0 [a,d]cycloh e p tene-S -carboxy late The carboxylic acid of Example I (4a) (4g.) was dissolved in 50 ml. of benzene and treated slowly with 10 ml. ofthionyl chloride. The mixture was refluxed for 18 hours and concentratedto a syrupy residue in vacuo which was taken up in benzene and againconcentrated to a syrup. The syrup was dissolved in 50 ml. of benzeneand cooled to 15. 1-diethylamino-2-propanol (3.9 g.) in 25 ml. ofbenzene was then added dropwise. The reaction mixture was stirred andrefluxed for 24 hours, cooled and treated with 50 ml. of 0.1 N sodiumhydroxide. The benzene was separated, washed with 50 ml. of cold water,dried over Na SO and evaporated. The residue was distilled and thefraction which distilled at 130/0.l5 mm. was collected. Yield: 1.1 g.

Analysis.For C H NO Calc"d: C, 78.61; H, 8.32; N, 3.98. Found: C, 78.57;H, 8.22; N, 3.94.

EXAMPLE VIII 2(]-piperidylethyl) 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-S-carboxylotehydrochloride monohydrate The carboxylic acid ofExample I (4a) (4 g., 0.016 mole) was dissolved in 50 ml. of benzene andtreated slowly with 10 ml. of thionyl chloride. The mixture was refluxedfor 18 hours and concentrated to a syrupy residue in vacuo. The residuewas taken up in benzene and again concentrated to a syrup. The syrup wasdissolved in 50 ml. of toluene, cooled to 5 C. and treated dropwise with3.8 g. (twice amount) of N-fl-hydroxyethyl piperidine in 25 ml. oftoluene. The reaction mixture was stirred and refluxed for 4 hours,cooled and treated with 50 ml. of water. The toluene layer wasseparated, washed with 50 ml. of cold water, dried over Na SO andevaporated to an oily residue. The oil was dissolved in ethyl acetateand treated (heat) with charcoal. After filtration, the ethyl acetatesolution was concentrated and a mixture of oil and crystals was obtainedwhich, after crystallization from ethyl acetate gave the desiredcompound which melted at 104105; yield: 0.7 g.

EXAMPLE IX Z-ethy laminoethyl 10,11-dihydro-5H-dibenzo[a,d] cyclohep tene-S-mrboxy late hydrochloride (1 N-ethyl-N-(Z-hydroxyethyl)10,1I-dihydro 5H-dibenzo [a,d] cyclohepzene-S-cm-boxamide.The carboxylicacid of Example I (4a) (4 g., 0.016 mole) was dissolved in 80 ml. ofbenzene and treated with 10 ml. of thionyl chloride. The mixture wasrefluxed for 18 hours and concentrated to a syrupy residue which wastaken up in benzene and again concentrated to a syrup. The syrup wasdissolved in 50 ml. of benzene and 2.7 g. (0.032 mole) twice the amountof 2-ethylaminoethanol in 20 ml. of benzene was added at roomtemperature. The reaction mixture was stirred and refluxed for 6 hours,cooled and treated with 25 ml. of water. The reaction mixture wasfiltered and after concentration of the filtrate an oil was obtained.After crystallization from ethyl-acetate the desired compound wasobtained which melted at 114-115; yield: 1.5 g.

Analysis.For C H NO Calcd: C, 77.58; H, 7.79; N, 4.51. Found: C, 77.15;H, 7.49; N, 4.78.

(2) Z-ethylaminoethyl 10,11-dihydr-5H-diben2o[a,d]cycloheptene--carboxylate hydrochloride-N ethyl-N- (2hydroxyethyl)-10,11-dihydro-SH-dibenzo[a,d] cycloheptene-S-carboxamide(1.9 g.) was suspended in 0.62 g. of concentrated hydrochloric acid. Themixture was warmed at 80 for 30 minutes, cooled and diluted with 20 ml.of ethanol. The mixture was concentrated in vacuo and the residue wasrecrystallized from a mixture of ethyl acetate and alcohol (7:3). Theproduct melted at 182- 183; yield 1.2 g.

Analysis.-For C H ClNO Calcd: C, 69.45; H, 6.99; N, 4.05. Found: C,69.18; H, 7.12; N, 3.93.

What is claimed is:

1. A compound of the formula H CONHBNRR:

wherein B represents lower alkylene R and R are hydrogen or lower alkylor, when taken together with the adjacent nitrogen, piperidino, pyrroli-5 dino, piperazino, N-(lower)alkylpiperazino, morpholino orthiomorpholino, the pharmaceutically acceptable acid addition saltsthereof or the pharmaceutically acceptable quaternary ammonium saltsthereof.

2. N-Z-(diethylaminoethyl) 10,11-dihydr0-5H-dibenz 10[a,d]cycloheptene-S-carboxamide.

References Cited UNITED STATES PATENTS 2,089,985 8/ 1937 Ruigh 260294.32,262,754 11/1941 Burtner 260294.3 2,316,051 4/1943 Cusic 260294.32,607,777 8/ 1952 Burtner et al 260294.3 2,659,725 11/1953 Cusic et a1260294.3

2,948,732 8/1960 Shindler. 3,142,681 7/1964 Davis 260294.3

FOREIGN PATENTS 616,907 4/1962 Belgium.

OTHER REFERENCES Davis et al.: J. Med. Chem., volume 7, pages 88 to 941964.

WALTER A. MODANCE, Primary Examiner.

A. D. SPEVACK, Assistant Examiner.

1. A COMPOUND OF THE FORMULA 2.N-I-(DIETHYLAMINOETHYL)-10,11-DIHYDRO-5H-DIBENZ(A,D)CYCLOHEPTENE-5-CARBOXAMIDE.